KR100331529B1 - Composition for Oral Administration of Hardly Soluble Antifungal Agent and Process for the Preparation Thereof - Google Patents

Composition for Oral Administration of Hardly Soluble Antifungal Agent and Process for the Preparation Thereof Download PDF

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KR100331529B1
KR100331529B1 KR1019990022472A KR19990022472A KR100331529B1 KR 100331529 B1 KR100331529 B1 KR 100331529B1 KR 1019990022472 A KR1019990022472 A KR 1019990022472A KR 19990022472 A KR19990022472 A KR 19990022472A KR 100331529 B1 KR100331529 B1 KR 100331529B1
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itraconazole
composition
present invention
phosphoric acid
preparation
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KR20010002590A (en
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우종수
이홍기
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민경윤
한미약품공업 주식회사
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    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/143Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with inorganic compounds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K31/00Medicinal preparations containing organic active ingredients
    • A61K31/33Heterocyclic compounds
    • A61K31/395Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins
    • A61K31/40Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine, rifamycins having five-membered rings with one nitrogen as the only ring hetero atom, e.g. sulpiride, succinimide, tolmetin, buflomedil
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/145Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic compounds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/14Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/141Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers
    • A61K9/146Intimate drug-carrier mixtures characterised by the carrier, e.g. ordered mixtures, adsorbates, solid solutions, eutectica, co-dried, co-solubilised, co-kneaded, co-milled, co-ground products, co-precipitates, co-evaporates, co-extrudates, co-melts; Drug nanoparticles with adsorbed surface modifiers with organic macromolecular compounds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841Filling excipients; Inactive ingredients
    • A61K9/485Inorganic compounds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841Filling excipients; Inactive ingredients
    • A61K9/4858Organic compounds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/4841Filling excipients; Inactive ingredients
    • A61K9/4866Organic macromolecular compounds
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL, OR TOILET PURPOSES
    • A61K9/00Medicinal preparations characterised by special physical form
    • A61K9/48Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/5073Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings
    • A61K9/5078Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals having two or more different coatings optionally including drug-containing subcoatings with drug-free core

Abstract

본 발명은 생체이용률이 증가된, 이트라코나졸을 비롯한 난용성 항진균제를 함유하는 경구투여용 조성물에 관한 것으로, 상세하게는 이트라코나졸과 같은 난용성 항진균제 및 인산의 용융분산체, 및 약제학적으로 허용되는 첨가제를 포함하는 항진균제의 경구투여용 조성물에 관한 것이다. The present invention I, including the itraconazole the bioavailability is increased, on the oral dosage composition containing a poorly soluble antifungal agents, particularly I, such as itraconazole additives acceptable melt dispersion, and a pharmaceutically soluble antifungal agents, and phosphoric acid It relates to a composition for oral administration of an antifungal agent comprising. 또한, 본 발명은 (a) 이트라코나졸 등의 난용성 항진균제와 인산을 혼화한 후 이를 100 내지 170℃가 되도록 가열하여 균질하게 용융시키고, (b) 이 용융물을 냉각시키면서 약제학적 첨가제를 첨가하고, (c) 이 혼합물을 실온에서 고결시켜 고형화한 후 분쇄하는 단계를 포함하는, 난용성 항진균제의 경구투여용 조성물의 제조 방법에 관한 것이다. In addition, the present invention is (a) after mixing a poorly soluble antifungal, and phosphoric acid, such as itraconazole and homogeneously melted by this heating to 100 to 170 ℃, (b) adding a pharmaceutical additive, while cooling the melt, and ( c) the mixture comprises the step of pulverization after solidification by cementation at room temperature, i relates to a method for oral administration of the poorly soluble antifungal drug composition. 본 발명의 항진균제로서는 이트라코나졸이 특히 바람직하며, 본 발명에 따른 이트라코나졸 함유 제제는 이트라코나졸의 물에 대한 용해도가 증가되어 생체이용률이 현저하게 증가된다. Itraconazole as an antifungal agent is particularly preferred in the present invention, and itraconazole-containing preparations according to the present invention is increasing the solubility of itraconazole in water is significantly increased bioavailability. 또한 본 발명의 방법에 따르면 용융분산체의 제조시 용융과정이 비교적 낮은 온도에서 수행될 뿐 아니라 제조공정이 용이한 장점이 있다. There is also the advantage of a manufacturing process, as well as easy to be carried out at a relatively low temperature manufacturing process of melting of the molten dispersion according to the method of the present invention.

Description

난용성 항진균제의 경구투여용 조성물 및 그의 제조 방법{Composition for Oral Administration of Hardly Soluble Antifungal Agent and Process for the Preparation Thereof} I composition for oral administration of the poorly soluble antifungal agent and its preparation method {Composition for Oral Administration of Hardly Soluble Antifungal Agent and Process for the Preparation Thereof}

본 발명은 생체이용률이 증가된, 이트라코나졸을 비롯한 난용성 항진균제를 함유하는 경구투여용 조성물 및 그의 제조 방법에 관한 것이다. The present invention I, including the itraconazole bioavailability of this increase relates to an oral composition and method for its preparation containing a poorly soluble antifungal agents. 더욱 구체적으로는, 이트라코나졸과 같은 난용성 항진균제 및 인산의 용융분산체, 및 약제학적으로 허용되는 첨가제를 포함하는, 난용성 항진균제의 경구투여용 조성물 및 그의 제조 방법에 관한 것이다. More specifically, I, such as itraconazole relates to a method I for oral administration of the poorly soluble antifungal compositions and their preparation comprising an additive acceptable as a melt dispersion, and a pharmaceutically soluble antifungal agents, and phosphoric acid.

본 발명은 다양한 난용성 항진균제에 적용될 수 있으며, 특히 바람직하게는 아졸계 항진균제인 이트라코나졸에 대해 적용될 수 있다. The present invention can be applied for a variety of I can be applied to a poorly soluble antifungal, and particularly preferably from azole antifungal drug itraconazole. 난용성 항진균제로서의이트라코나졸은 우수한 항진균 활성에도 불구하고 난용성이어서 경구투여될 경우 생체이용률이 저조하다는 단점이 있다. I there is a disadvantage that availability of itraconazole as an antifungal agent was poor bioavailability when administered orally, and then poorly soluble in spite of excellent antifungal activity. 실제로 이트라코나졸의 물에 대한 용해도는 1 ㎍/㎖이하이고, pKa 값이 3.7이어서 매우 낮은 pH에서만 이온화되어 용해된다. Is actually a solubility of itraconazole in water is less than 1 ㎍ / ㎖, then pKa value of 3.7 is dissolved is ionized only at very low pH. 또한 경구투여된 이트라코나졸의 생체이용률(흡수 또는 혈중 농도)은 개체에 따라 편차가 크며, 섭취된 음식물의 영향을 크게 받는 것으로 알려져 있다. In addition, the bioavailability (absorption or blood levels) of the administered oral itraconazole are large variations depending on the object, it is largely known to be affected by the intake of food.

따라서, 이트라코나졸의 물에 대한 용해도를 증가시켜 생체이용률을 증가시키기 위한 시도로서 이트라코나졸과 사이클로덱스트린의 포접 화합물을 사용하는 방법이 시도된 바 있으나(국제공개 제 85/002767 호 및 미국특허공보 제 4,764,604 호), 이 방법은 이트라코나졸의 물에 대한 용해도를 거의 개선시키지 못하고 있을 뿐만 아니라, 실제 생산공정에 있어서도 포접물 형성을 위해 여러단계의 복잡한 공정을 필요로 하기 때문에 바람직하지 못하다. Thus, by increasing the solubility of itraconazole in water is an attempt to increase the bioavailability attempted using the inclusion compound of itraconazole and a cyclodextrin, but bar (International Publication No. 85/002767 and U.S. Patent No. 4,764,604 No. ), the method not only does not substantially improved the solubility of itraconazole in water, to form also included jeopmul the actual production process, it is not preferable because it requires a complicated process of several steps.

최근에는 약학적으로 불활성 또는 중성의 설탕, 덱스트린, 전분 등으로 이루어진 코아 위에 이트라코나졸과 친수성 고분자가 코팅되고 다시 그 위에 폴리에틸렌글리콜 등의 고분자로 코팅된 3층 구조의 비드가 얀센사에 의해 개발되어 시판되고 있다(국제공개 제 94/05263 호, 제품명; 스포라녹스 캅셀). Recently, commercially available pharmaceutically inert or neutral sugar, dextrin, beads of a three-layer structure is coated with a polymer such as itraconazole and a hydrophilic polymer is coated again with the above polyethylene glycol on a core made of a starch and the like have been developed by Janssen Inc. is (International Publication No. 94/05263 number, product name; seuporanokseu capsule). 그러나 이 방법은 직경 600 내지 700 ㎛인 작은 코아를 사용하므로 코팅과정중에 뭉치는 현상이 발생하는 등 생산공정상의 어려움이 있다. However, this method has a difficulty in the production process, such as a sheaf of the developer in the coating process occurs because using a small core diameter of 600 to 700 ㎛.

한편, 이트라코나졸의 생체이용률이 증가되고 기존 시판제제의 문제점이던 음식물에 의한 영향을 거의 받지 않는 제제로, 용융-압출(melt-extrusion) 방법에 따라 이트라코나졸과 히드록시프로필 메틸셀룰로오스 등의 수용성 고분자 혼합물을245 내지 265 ℃로 가열하여 용융된 이트라코나졸을 용융되지 않은 수용성 고분자에 분산시킨 고체분산체(solid dispersion)가 개발된 바 있으나(국제공개 제 97/44014 호, 제품명; 스포라녹스 정, 얀센), 이트라코나졸의 용융-압출 과정이 245 내지 265 ℃의 고온에서 수행되어야 하고, 또한 용융된 이트라코나졸을 고분자에 매우 균일하게 분산시켜야 하는 등 용융압출물의 제조에 어려움이 있고, 더 나아가 용융되지 않은 이트라코나졸이 잔존하면서 용출이나 흡수에 영향을 미칠 수 있어 재현성있는 제품을 얻기가 어렵다는 단 On the other hand, the bioavailability of itraconazole is increased and as a preparation that is almost not affected by diet which was a problem of the conventional commercially available preparations, melting - a water-soluble polymer blend such as extrusion (melt-extrusion) according to the method of itraconazole and hydroxypropylmethylcellulose heated to a development in which the solid dispersion (solid dispersion) dispersion in a water-soluble polymer is not melted by the molten itraconazole 245 to 265 bar, but ℃ (International Publication No. 97/44014 number, product name; seuporanokseu tablets, Janssen), of itraconazole the melt-extrusion process is to be performed at a high temperature of 245 to 265 ℃, and further it is difficult to manufacture a molten extrudate, etc. that must be very uniformly dispersed in the molten itraconazole in the polymer, and further unmelted itraconazole remains dissolution or obtain reproducible product that can affect the absorption stage is difficult 점이 있다. There point. 더구나, 흡수율 증가에 대한 구체적인 사실은 아직 확인되지 않고 있다. Moreover, the specific facts of the absorption rate increase has not yet been identified.

이트라코나졸과 같은 난용성의 항진균제를 포함하는 경구투여용 조성물의 유용한 제제를 얻기 위해서는, 제제에 포함된 난용성 항진균제가 생체내에서 흡수되기에 충분한 속도로 용출되는 등 제제학적 유용성이 먼저 인정되어야 한다. I such as itraconazole in order to obtain a useful preparation for oral administration of a composition comprising an antifungal agent of the availability, the formulation significant utility, such as a poorly soluble antifungal agents included in the formulations to be eluted at a rate sufficient to be absorbed in the body must be recognized first. 그러나, 아직까지는 이러한 유용성을 만족시키는 난용성 항진균제의 경구투여용 조성물이 보고된 바 없다. However, to still satisfy this availability until I have the composition is for oral administration of the poorly soluble antifungal reported.

이에 본 발명자들은 이트라코나졸 등의 난용성 항진균제와 용융물을 쉽게 형성하므로 제조시 완전한 용해가 이루어져 제조공정이 용이하고 재현성 있게 제제 내의 난용성 항진균제의 용해도를 증가시킬 수 있는 새로운 용융 담체를 개발하기 위해 다양한 연구를 수행하였으며, 그 결과 무기산인 인산이 난용성 항진균제, 특히 이트라코나졸과 쉽게 용융분산체를 형성하고 결정구조에 변화를 주어 용출을 현저히 증가시킬 수 있음을 확인하고 본 발명을 완성하였다. The variety of the present inventors I, such as itraconazole to develop a new molten carrier to increase the I solubility of poorly soluble antifungal agents in allowing easy manufacturing process, the complete dissolution time of manufacture made it easy to form a poorly soluble antifungal, and melt and reproducible preparation studies a was carried out, it was confirmed that as a result the inorganic acid is phosphoric acid I can significantly increase the soluble antifungal drug, in particular itraconazole eluted given a change in the easy to form a molten dispersion of the crystal structure, and have completed the present invention.

따라서, 본 발명의 목적은 생체이용률이 증가된, 이트라코나졸을 비롯한 난용성 항진균제의 경구투여용 조성물 및 그의 제조 방법을 제공하는 것이다. It is therefore an object of the present invention I, including the itraconazole bioavailability increased to provide an oral dosage composition for and a method of producing a soluble antifungals.

도 1은 본 발명의 이트라코나졸 제제의 생체 이용률을 시판되는 대조 제제(스포라녹스 R )와 비교하여 나타낸 것이다. Figure 1 shows in comparison to the control drug (seuporanokseu R) as marketed bioavailability of itraconazole formulation of the present invention.

상기 목적에 따라, 본 발명에서는 이트라코나졸과 같은 난용성 항진균제 및 인산의 용융분산체, 및 약제학적으로 허용되는 첨가제를 포함하는 난용성 항진균제 함유 경구투여용 조성물을 제공한다. In accordance with one aspect, the present invention, such as I and I itraconazole comprising an additive acceptable as a melt dispersion, and a pharmaceutically soluble antifungal agents, and phosphoric acid provides a composition for oral administration containing poorly soluble antifungal agents.

본 발명의 난용성 항진균제로서는 이트라코나졸이 특히 바람직하다. I of the present invention are itraconazole is particularly preferred as the soluble antifungals.

본 발명의 제제에서 용융 담체로는 인산이 사용될 수 있다. In the preparation of the present invention in a molten carrier may be used are phosphoric acid. 인산은 난용성 항진균제, 특히 이트라코나졸의 용출을 현저히 증가시키며 제제화시 고형상태를 잘 형성할 수 있어 바람직하게 본 발명에 사용될 수 있다. Phosphate I can be used in the present invention preferably can be well formed in the solid state when formulated sikimyeo significantly increase the soluble antifungal drug, in particular itraconazole eluted.

상기 용융분산체에 포함되는 난용성 항진균제와 인산의 혼합비는 중량비로 1:0.1 내지 1:10이고, 1:0.5 내지 1:5가 바람직하다. The mixing ratio of the poorly soluble antifungal agents and phosphoric acid contained in the molten dispersion is in a weight ratio 1: 0.1 to 1: 10, 1: 0.5 to 1: 5 are preferred.

본 발명에서 사용할 수 있는 약제학적으로 허용되는 첨가제로는, 상기 용융분산체의 경구투여용 고형제제의 분말성을 증가시키기 위해 약제학적 분야에서 통상적으로 사용되는 것이면 무엇이나 사용될 수 있으며, 대표적인 예로는 락토오즈, 덱스트린, 전분, 미세결정 셀룰로오스, 히드록시프로필메틸 셀룰로오스, 히드록시프로필 셀룰로오스, 히드록시에틸 셀룰로오스, 에틸셀룰로오스, 메틸셀룰로오스, 폴리에틸렌글리콜, 이산화규소, 하이드로탈사이트, 알루미늄 마그네슘 실리케이트,수산화 알루미늄, 알루미늄 실리케이트, 마그네슘 알루미늄 메타실리케이트, 벤토나이트 및 이들의 혼합물 등을 들 수 있다. Additives in a pharmaceutically acceptable to be used in the present invention, and do as long as it is commonly used in the pharmaceutical field and can be used to increase the powder of the solid preparation for oral administration of the molten dispersion, typical examples of lactose, dextrin, starch, microcrystalline cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl cellulose, methyl cellulose, polyethylene glycol, silicon dioxide, hydrotalcite, aluminum magnesium silicate, aluminum hydroxide, It includes aluminum silicate, magnesium aluminum metasilicate, bentonite and a mixture thereof.

또한 본 발명의 조성물은 용융분산체 및 담체 외에, 생체내 투여시 수용성 매질과 접촉하여 신속히 붕해, 용출될 수 있도록 계면활성제를 추가로 포함할 수 있으며, 이 계면활성제의 대표적인 예는 다음과 같다: In addition, compositions of the invention in addition to the molten dispersion and a carrier, in vivo when administered into contact with an aqueous medium may further comprise a surface active agent so that they can be quickly disintegration, dissolution, representative examples of the surface active agent is as follows:

(1) 천연 또는 수소화 식물성 오일과 에틸렌 글리콜의 반응 생성물: (1) reaction products of natural or hydrogenated vegetable oils and ethylene glycol are:

예를 들어, 폴리옥시에틸렌 글리콜화된 천연 또는 수소화된 피마자유(제품명: Cremophor R , BASF), For example, polyoxyethylene glycol screen natural or hydrogenated castor oil (trade name: Cremophor R, BASF),

(2) 폴리옥시에틸렌-소르비탄-지방산 에스테르류: (2) polyoxyethylene-sorbitan-fatty acid esters:

모노 또는 트리 라우릴, 팔미틸, 스테아릴 또는 올레일의 에스테르(제품명: Tween, ICI), Mono-or tri- lauryl, palmityl, stearyl or oleyl ester (trade name: Tween, ICI),

(3) 폴리옥시에틸렌 지방산 에스테르류: (3) polyoxyethylene fatty acid esters:

폴리옥시에틸렌 스테아르산 에스테르(제품명: Myrj), Polyoxyethylene stearic acid ester (trade name: Myrj),

(4) 폴리옥시에틸렌-폴리옥시프로필렌 블록 공중합체(제품명: Poloxamer), (4) polyoxyethylene-polyoxypropylene block copolymer (trade name: Poloxamer),

(5) 소듐 디옥틸설포숙시네이트 또는 소듐 라우릴 설페이트, (5) sodium dioctyl tilseol sulfosuccinates or sodium lauryl sulphate,

(6) 인지질류, (6) phospholipids,

(7) 프로필렌 글리콜 모노-지방산 에스테르 또는 프로필렌 글리콜 디-지방산 에스테르류: (7) propylene glycol mono-fatty acid ester or propylene glycol di-fatty acid esters:

프로필렌 글리콜 디카프릴레이트, 프로필렌 글리콜 디라우레이트, 프로필렌 글리콜 이소스테아레이트, 프로필렌 글리콜 라우레이트, 프로필렌 글리콜 리시노레이트, 프로필렌 글리콜 카프릴릭-카프릭산 디에스테르(제품명: Miglyol 840), Propylene glycol dicarboxylic frill rate, propylene glycol dilaurate, propylene glycol isostearate, propylene glycol laurate, propylene glycol Li Sino acrylate, propylene glycol Caprylic-capric acid diester (product name: Miglyol 840),

(8) 천연 식물성 오일 트리글리세리드 및 폴리알킬렌 폴리올의 트랜스-에스테르화 반응산물(제품명: Labrafil M), (8) trans-natural vegetable oil triglyceride and a polyalkylene polyol esterification reaction product (product name: Labrafil M),

(9) 모노-, 디- 또는 모노/디-글리세리드: (9) mono-, di-or mono / di-glycerides:

카프릴릭/카프릭산 모노- 또는 디-글리세리드(제품명: Imwitor), Caprylic / capric acid mono- or di-glyceride (trade name: Imwitor),

(10) 소르비탄 지방산 에스테르: (10) sorbitan fatty acid esters

소르비탄 모노라우릴, 소르비탄 모노팔미틸, 소르비탄 모노스테아릴(제품명: Span). Sorbitan lauryl, palmityl sorbitan, sorbitan stearyl (trade name: Span).

상기에 나열한 계면활성제 중, 특히 수소화 식물성 오일의 폴리옥시에틸렌 생성물, 폴리옥시에틸렌-폴리옥시프로필렌 블록 공중합체 및 폴리옥시에틸렌-소르비탄 지방산 에스테르가 바람직하다. Of surfactants listed above, in particular poly oxyethylene product of hydrogenated vegetable oils, polyoxyethylene-polyoxypropylene block copolymers and polyoxyethylene-sorbitan fatty acid esters it is preferred.

본 발명의 조성물은 분말, 과립, 정제, 코팅제제, 액상제제 등으로 제형화될 수 있는데, 예를 들어, 용융분산체에 활택제 및 기타 약제학적 첨가제 등을 첨가하여 분말 또는 과립의 형태로 경질캅셀에 충진하거나 타정에 필요한 약제학적 첨가제를 첨가하여 정제로 타정하는 방법, 용융분산체를 수용액 상태로 용해시켜 액상제제로 제제화하는 방법, 용융분산체를 액상 상태에서 논파렐(non-pareil)과 같은 설탕 비드에 코팅하는 방법 또는 용융분산체를 고형담체와 혼화하고 냉각시켜 제제화하여 경질캅셀로 제조하는 방법에 따라 제형화될 수 있다. There composition of the present invention can be formulated into powders, granules, tablets, coating agents, liquid preparations such as, for example, light in the melt dispersion in the form of powder or granule by addition of such a lubricant and other pharmaceutical additives filled in capsules, or by the addition of the pharmaceutical additive necessary for the compression method of determining the other tablets, and dissolving the melt-dispersion in aqueous solution how to formulate a liquid preparation, the molten dispersion of the non Farrell (non-pareil) in a liquid state the method or melt dispersion coated on sugar beads, such may be formulated according to the method for producing a hard capsule was formulated by mixing the solid carrier and allowed to cool.

본 발명의 용융분산체는, (a) 이트라코나졸과 같은 난용성 항진균제와 인산을 혼화한 후 이를 100 내지 170℃가 되도록 가열하여 균질하게 용융시키고, (b)이 용융물을 냉각시키면서 약제학적 첨가제를 첨가하고, (c) 이 혼합물을 실온에서 고결시켜 고형화한 후 분쇄하여 제조할 수 있다. Melt-dispersion of the present invention, (a) I, such as itraconazole and homogeneously melted by being heated to 100 to 170 ℃ it after mixing the poorly soluble antifungal agents and phosphoric acid, (b) adding a pharmaceutical additive, while cooling the melt and then (c) solidifying the mixture to anti-bonding at room temperature can be prepared by grinding. 또한, 여기에 추가로 약제학적 첨가제를 첨가하여 최종 제형을 제조할 수 있다. Further, it is possible to manufacture the final formulation by the addition of this additional pharmaceutical additives in.

다른 방법으로는, 유기용매를 사용하여 용융분산체를 만드는 방법으로 주성분인 이트라코나졸 등의 난용성 항진균제를 인산과 혼화한 후 여기에 소량의 유기용매, 예를 들어 에탄올, 메틸렌클로라이드, 클로르포름 등을 가하여 상온에서 용해시키고 기타 약제학적 첨가제를 가한 후 서서히 열을 가하면서 유기용매를 증발시켜 최종 용융분산체를 얻을 수 있다. The alternative, such as the main component of itraconazole by the method using an organic solvent to create a molten dispersion I in a small amount of an organic solvent herein after mixing a poorly soluble antifungal, and phosphoric acid, for example, ethanol, methylene chloride, chloroform after dissolution was added at room temperature and added to other pharmaceutical additives evaporating the organic solvent while applying heat gradually to obtain the final dispersion melt.

이하 본 발명을 실시예에 의하여 상세히 설명하나, 본 발명이 이에 한정되는 것은 아니다. Described in detail below by the present invention in one embodiment, the present invention is not limited thereto.

실시예 1: 경질캅셀제의 제조 Example 1: Preparation of hard capsule

성 분 함량(mg/제제) Ingredient Content (mg / preparation)

이트라코나졸 100 Itraconazole 100

인산 85% 150 Phosphoric acid 85% 150

폴록사머 F127 30 Poloxamer F127 30

히드록시프로필메틸 셀룰로오스 20 Hydroxypropylmethylcellulose 20

크레모포어 RH40 10 Cradles mode pore RH40 10

하이드로탈사이트 70 Hydrotalcite 70

이산화규소 20 Silicon Dioxide 20

용융 분산 담체인 인산과 활성성분인 이트라코나졸을 혼합한 후 약 160℃ 정도로 열을 가해 용융시켰다. Then a solution of the carrier in the molten dispersion of the active ingredient itraconazole with phosphoric acid was applied to the column at about 160 ℃ melt. 이후 자연냉각 시키면서 이 용융물에 폴록사머 F127, 크레모포어 RH40을 가하고 히드록시프로필메틸 셀룰로오스, 하이드로탈사이트 등을 가해 고결시켰다. After the natural cooling was applied integrity while in the melt was added the poloxamer F127, Crescent mode pore RH40 hydroxypropylmethylcellulose, hydrotalcite and the like. 이 고결시킨 고형물에 이산화규소를 가하여 분쇄하고 경질캅셀에 충진하여 제제화하였다. Obtaining the silicon dioxide in which the anti-caking solid which was formulated by filling a hard capsule.

실시예 2: 경질캅셀제의 제조 Example 2: Preparation of hard capsule

성 분 함량(mg/제제) Ingredient Content (mg / preparation)

이트라코나졸 100 Itraconazole 100

인산 85% 100 Phosphoric acid 85% 100

폴록사머 F127 30 Poloxamer F127 30

트윈 80 10 Tween 80 10

히드록시프로필메틸 셀룰로오스 20 Hydroxypropylmethylcellulose 20

하이드로탈사이트 70 Hydrotalcite 70

이산화규소 20 Silicon Dioxide 20

상기 성분들을 사용하여 실시예 1의 제조 방법과 동일하게 경질캅셀제를 제조하였다. The same as the manufacturing method of Example 1 using the ingredients to prepare a hard capsule.

실시예 3: 경질캅셀제의 제조 Example 3: Preparation of hard capsule

성 분 함량(mg/제제) Ingredient Content (mg / preparation)

이트라코나졸 100 Itraconazole 100

인산 85% 100 Phosphoric acid 85% 100

폴록사머 F127 30 Poloxamer F127 30

크레모포어 RH40 10 Cradles mode pore RH40 10

하이드로탈사이트 100 Hydrotalcite 100

이산화규소 20 Silicon Dioxide 20

상기 성분들을 사용하여 실시예 1의 제조 방법과 동일하게 경질캅셀제를 제조하였다. The same as the manufacturing method of Example 1 using the ingredients to prepare a hard capsule.

실시예 4: 경질캅셀제의 제조 Example 4: Preparation of hard capsule

성 분 함량(mg/제제) Ingredient Content (mg / preparation)

이트라코나졸 100 Itraconazole 100

인산 85% 150 Phosphoric acid 85% 150

트윈 80 20 Tween 80 20

크레모포어 RH40 10 Cradles mode pore RH40 10

하이드로탈사이트 70 Hydrotalcite 70

이산화규소 20 Silicon Dioxide 20

상기 성분들을 사용하여 실시예 1의 제조 방법과 동일하게 경질캅셀제를 제조하였다. The same as the manufacturing method of Example 1 using the ingredients to prepare a hard capsule.

실시예 5: 경질캅셀제의 제조 Example 5: Preparation of hard capsule

성 분 함량(mg/제제) Ingredient Content (mg / preparation)

이트라코나졸 100 Itraconazole 100

인산 85% 50 Phosphoric acid 85% 50

폴록사머 F127 40 Poloxamer F127 40

크레모포어 RH40 20 Cradles mode pore RH40 20

하이드로탈사이트 70 Hydrotalcite 70

이산화규소 20 Silicon Dioxide 20

상기 성분들을 사용하여 실시예 1의 제조 방법과 동일하게 경질캅셀제를 제조하였다. The same as the manufacturing method of Example 1 using the ingredients to prepare a hard capsule.

실시예 6: 경질캅셀제의 제조 Example 6: Preparation of hard capsule

성 분 함량(mg/제제) Ingredient Content (mg / preparation)

이트라코나졸 100 Itraconazole 100

인산 85% 150 Phosphoric acid 85% 150

폴록사머 F127 30 Poloxamer F127 30

크레모포어 RH40 10 Cradles mode pore RH40 10

폴리에틸렌글리콜 20000 150 Polyethylene glycol 000 150

이산화규소 20 Silicon Dioxide 20

상기 성분들을 사용하여 실시예 1의 제조 방법과 동일하게 경질캅셀제를 제조하였다. The same as the manufacturing method of Example 1 using the ingredients to prepare a hard capsule.

실시예 7: 경질캅셀제의 제조 Example 7: Preparation of hard capsule

성 분 함량(mg/제제) Ingredient Content (mg / preparation)

이트라코나졸 100 Itraconazole 100

인산 85% 100 Phosphoric acid 85% 100

폴록사머 F127 100 Poloxamer F127 100

크레모포어 RH40 50 Cradles mode pore RH40 50

폴리에틸렌글리콜 20000 200 Polyethylene glycol 000 200

용융 분산 담체인 인산과 활성성분인 이트라코나졸을 혼합한 후 여기에 에탄올 약 500 mg을 가해 실온에서 용해시켰다. Then a solution of the carrier in the molten dispersion of the active ingredient itraconazole and phosphoric acid added to about 500 mg of ethanol here was dissolved at room temperature. 여기에 약간의 미열을 가할 경우 용해속도를 증가시킬 수 있다. Here it is possible to increase the rate of dissolution when added to some of the low grade fever. 이후 이 용해물에 폴록사머 F127, 크레모포어 RH40을 가하고 마지막으로 미리 약 65℃에서 녹인 폴리에틸렌글리콜 20000을 가해 혼합한후 냉각하면서 고결시켰다. Since the anti-caking was added while cooling and then the poloxamer F127, Crescent mode pore RH40 to melt a mixture of polyethylene glycol 20000 is applied to the pre-melted at about 65 ℃ last for. 이 고결시킨 고형물을 분쇄하고 경질캅셀에 충진하여 제제화하였다. This was caking solid was crushed and formulated by filling a hard capsule.

실시예 8: 경질캅셀제의 제조 Example 8 Preparation of hard capsules

성 분 함량(mg/제제) Ingredient Content (mg / preparation)

이트라코나졸 100 Itraconazole 100

인산 85% 200 Phosphoric acid 85% 200

폴리에틸렌글리콜 20000 100 Polyethylene glycol 000 100

크레모포어 RH40 20 Cradles mode pore RH40 20

설탕비드 400 Sugar beads 400

실시예 7의 제조방법과 동일하게 이트라코나졸, 인산 및 에탄올을 가해 용액을 만든 후 폴리에틸렌글리콜 반량, 크레모포어 RH40을 가해 용해시켰다. And then carried out in the same manner as the production process of Example 7 applied itraconazole, phosphoric acid and the solution made of ethanol and dissolved by applying half quantity of polyethylene glycol, Crescent mode pore RH40. 이 용액을 설탕비드에 골고루 코팅하면서 냉각시켰다. The solution was cooled while evenly coated on sugar beads. 이어서 코팅된 비드에 폴리에틸렌글리콜 잔량을 추가로 코팅하였다. It was then coated with the remaining amount added to the polyethylene glycol in the coating bead. 냉각된 코팅비드를 경질캅셀에 충진하여 제제화하였다. It was formulated by filling the cooled coated beads in a hard capsule.

비교예 Comparative Example

성 분 함량(mg/제제) Ingredient Content (mg / preparation)

이트라코나졸 100 Itraconazole 100

폴록사머 F127 30 Poloxamer F127 30

히드록시프로필메틸 셀룰로오스 20 Hydroxypropylmethylcellulose 20

크레모포어 RH40 10 Cradles mode pore RH40 10

하이드로탈사이트 70 Hydrotalcite 70

이산화규소 20 Silicon Dioxide 20

이트라코나졸을 약 170℃ 정도로 열을 가해 용융시켰다. It was melted by applying heat itraconazole to about 170 ℃. 이후 이 용융물에 폴록사머 F127, 크레모포어 RH40을 가하고 히드록시프로필메틸 셀룰로오스, 하이드로탈사이트 등을 가해 고결시켰다. Since the melt poloxamer F127, it was added to all pores Crescent RH40 was added anti-caking and the like hydroxypropylmethylcellulose, hydrotalcite. 이 고결시킨 고형물에 이산화규소를 가하여 분쇄하고 경질캅셀에 충진하여 제제화하였다. Obtaining the silicon dioxide in which the anti-caking solid which was formulated by filling a hard capsule.

시험예 1: 비교용출시험 Test Example 1: Comparison of the dissolution test

실시예 1 내지 3, 실시예 7, 비교예 1에서 제조된 제제와, 대조제제인 시판 이트라코나졸 제피과립(스포라녹스 캅셀, 얀센사) 및 용융정(스포라녹스 정, 얀센사)을 대한약전 일반시험법중 용출시험법 제 2 법(패들법)에 따라 시험하고, 45분 후 용출액을 취하여 용출된 양을 아래 분석법에 따라 시험하였다. Examples 1-3, Example 7 and Comparative Example and the prepared formulations in the first, the control drug commercially available itraconazole Jaffe granules (seuporanokseu capsule, Janssen, Inc.) and a melt tablets (seuporanokseu tablets, Janssen Inc.) Pharmacopoeia General Test Methods for the in the dissolution test method was tested in accordance with the amount eluted second method taking the test, and the leaching solution after 45 minutes according to (paddle method) in the following assay.

용출시험장치 : Erweka DT 80 Dissolution test apparatus: Erweka DT 80

용출액 : 0.1 N 염산 900 ml Eluent: 0.1 N hydrochloric acid 900 ml

용출액의 온도 : 37±0.5℃ Eluent temperature: 37 ± 0.5 ℃

회전속도 : 100±4 rpm Rotation speed: 100 ± 4 rpm

분석법 : 액체 크로마토그라피법 Method: liquid chromatography

칼 럼 - Cosmosil C 18 (150 ㎜×4.6 ㎜) Column - Cosmosil C 18 (150 ㎜ × 4.6 ㎜)

이동상 - 아세토니트릴 : pH 7.0 인산염 완충액(60:40) Mobile phase of acetonitrile: pH 7.0 phosphate buffer (60: 40)

주입량 - 10 ㎕ Dose - 10 ㎕

유 속 - 1.2 ㎖/분 In oil - 1.2 ㎖ / min

검출기 - UV 255 ㎚ Detector - UV 255 ㎚

그 결과는 하기 표 1과 같다. The results are shown in Table 1 below.

검체 Specimens 실시예 1 Example 1 실시예 2 Example 2 실시예 3 Example 3 실시예 7 Example 7 비교예 Comparative Example 스포라녹스 캅셀 Seuporanokseu capsule 스포라녹스 정 Seuporanokseu information
용출률(45분) Dissolution (45 minutes) 94% 94% 91% 91% 96% 96% 90% 90% 15% 15% 50% 50% 92% 92%

표 1에서 보듯이, 인산을 용융분산 담체로 사용한 본 발명의 제제들(실시예 1∼3 및 7)은 용융담체인 인산을 사용하지 않은 비교예의 제제에 비해 이트라코나졸의 용출률이 현저히 높으므로 이트라코나졸과 같은 난용성 항진균제의 용해성이 증가된 것을 확인할 수 있었다. As shown in Table 1, and the phosphoric acid preparation of the present invention using a molten dispersion carrier (Examples 1 to 3 and 7), since the dissolution rate of itraconazole is significantly higher compared to the formulation of the comparative example did not use a molten carrier of itraconazole and phosphoric acid as I was able to see that increase the solubility of poorly soluble antifungal agents. 나아가, 인산을 용융담체로 사용할 경우 기존의 용융제보다 저온에서 제제화할 수 있고 제조공정이 용이하므로 대량생산시 매우 유리한 장점이 있다. Furthermore, the use of phosphoric acid in a molten carrier may be formulated at a lower temperature than the conventional melt and facilitate the manufacturing process, so it is very advantageous in mass production.

시험예 2: 비교흡수시험 Test Example 2: Comparative Absorption Test

본 발명의 제제의 생체이용률을 평가하기 위해, 시험제제인 실시예 1의 제제와 대조제제인 시판 제제(스포라녹스 정, 얀센사)의 흡수시험을 실시하였다. In order to evaluate the bioavailability of the formulation of the present invention, the absorption test was carried out in the test of Example 1 formulation and the control formulation of a commercially available formulation (seuporanokseu tablets, Janssen g) of the formulation.

실험동물로는 스프라그-다우리계 웅성 랫트(체중 300g, 14-15 주령)를 검체당 각각 10 마리씩 사용하였으며, 랫트는 우리속에서 동일한 조건으로 4일 이상 일정한 통상의 랫트용 고체사료 및 물을 공급하여 사육하였다. Animals in the Sprague-We-based male rats (body weight 300g, 14-15 weeks old) were used for each of 10 rabbits per sample, the rats are solid feed and water for normal rats given 4 days under the same conditions in our It was bred by feeding. 48 시간이상 절식시킨 후 시험에 사용하였으며 절식시에는 물을 자유롭게 마실 수 있게 하였다. After fasting for 48 hours or more it was used for testing at the time of fasting were able to drink water freely.

랫트에 시험제제 또는 대조제제를 랫트 체중 1 kg당 이트라코나졸로서 20 mg 해당량으로 경구투여용 기구를 이용하여 물과 함께 밀어넣어 투여하였다. To the test formulation or the control formulation as rat body weight itraconazole per kg to rats using oral administration mechanism for the 20 mg dose was administered to the pushing it with water. 투여전, 투여후 2 시간, 4 시간, 6 시간, 8 시간 및 24 시간이 경과된 때에 각각 랫트의 심장에서 직접 채혈하였다. When a is 2 hours, 4 hours, 6 hours, 8 hours and 24 hours before administration, blood sample was collected after dosing has passed directly from the heart of each rat.

혈장 500 ㎕에 내부표준용액 50 ㎕(질산에코나졸 500 ㎍/㎖ 메탄올 용액) 및 1 M 탄산완충액(pH 10) 200 ㎕를 가하고 혼합한 후 추출용매(n-헵탄 : 이소아밀알콜 = 9 : 1) 7 ㎖를 가하고 진탕추출하였다. Internal standard in plasma 500 ㎕ solution 50 ㎕ (nitrate echo najol 500 ㎍ / ㎖ methanol solution) and 1 M carbonate buffer (pH 10) was added and then a solution of 200 ㎕ extraction solvent (n- heptane: isoamyl alcohol = 9: 1 ) was added and extracted with shaking for 7 ㎖. 이 액을 3,000 rpm에서 10분간 원심분리한 후 상등액 6 ㎖를 취해 50℃ 질소기류하에서 증발농축하였다. The liquid to take for 10 minutes and then centrifuged at 3,000 rpm for 6 ㎖ supernatant was concentrated 50 ℃ evaporated under a stream of nitrogen. 이 잔류물에 이동상 200 ㎕를 가하여 용해시킨 후 HPLC를 다음과 같이 실시하였다. It was dissolved in 200 ml of mobile phase ㎕ the residue was subjected to HPLC as follows.

칼럼: Inertsil ODS2(4.6×250 ㎜, 5 ㎛) Column: Inertsil ODS2 (4.6 × 250 ㎜, 5 ㎛)

이동상: 0.05 % 트리에틸아민이 포함된 65% 아세토니트릴 수용액 Mobile phase: 0.05% triethylamine and 65% aqueous acetonitrile solution containing the

주입용량: 100 ㎕ Injection volume: 100 ㎕

유속: 1.2 ㎖/분 Flow rate: 1.2 ㎖ / min

검출: 258 nm Detection: 258 nm

그 결과는 도 1과 같다. The results are shown in Figure 1; 도 1에서 보듯이, 본 발명에 따른 실시예 1의 제제는 시판제제와 비교할 때 동등 이상의 증가된 생체이용률을 나타낸다. As shown in FIG. 1, the formulation of Example 1 according to the present invention exhibit increased bioavailability at least equivalent as compared to the commercially available formulation.

본 발명의 제제는 이트라코나졸을 비롯한 난용성 항진균제와 인산의 용융분산체를 사용함으로써 제제 내의 난용성 항진균제의 물에 대한 용해도가 증가되어 생체이용률이 현저하게 증가된다. The formulation of the present invention is I increases the solubility in water of poorly soluble antifungal agents in the I, including the preparation of itraconazole by using a molten dispersion of the poorly soluble antifungal agents and phosphoric acid is significantly increased bioavailability.

또한 본 발명에 따르면 용융분산체의 제조시 용융과정이 비교적 낮은 온도에서 수행될 뿐 아니라 제조공정이 용이한 장점이 있다. There are also produced during melting process is relatively easy and the manufacturing process as well as the advantages to be performed at a temperature of the molten dispersion according to the present invention.

Claims (6)

  1. 이트라코나졸 및 인산의 용융분산체, 및 약제학적으로 허용되는 첨가제를 포함하는 이트라코나졸의 경구투여용 조성물. Itraconazole and phosphoric acid in the melt dispersion, and the oral dosage composition of itraconazole comprising an additive which is pharmaceutically acceptable.
  2. 제 1 항에 있어서, According to claim 1,
    이트라코나졸과 인산의 혼합비가 중량비로 1:0.1 내지 1:10인 조성물. In a mixing ratio of itraconazole and phosphoric acid weight ratio of 1: 0.1 to 1: 10 of composition.
  3. 제 1 항에 있어서, According to claim 1,
    상기 약제학적으로 허용되는 첨가제가 락토오즈, 덱스트린, 전분, 미세결정 셀룰로오스, 히드록시프로필메틸 셀룰로오스, 히드록시프로필 셀룰로오스, 히드록시에틸 셀룰로오스, 에틸셀룰로오스, 메틸셀룰로오스, 폴리에틸렌글리콜, 이산화규소, 하이드로탈사이트, 알루미늄 마그네슘 실리케이트, 수산화 알루미늄, 알루미늄 실리케이트, 마그네슘 알루미늄 메타실리케이트, 벤토나이트 및 이들의 혼합물로 이루어진 군으로부터 선택된 조성물. The acceptable additives to the pharmaceutical, lactose, dextrin, starch, microcrystalline cellulose, hydroxypropyl methyl cellulose, hydroxypropyl cellulose, hydroxyethyl cellulose, ethyl cellulose, methyl cellulose, polyethylene glycol, silicon dioxide, hydrotalcite , magnesium aluminum silicate, aluminum hydroxide, aluminum silicate, magnesium aluminum metasilicate, bentonite and a composition selected from the group consisting of a mixture thereof.
  4. 제 1 항에 있어서, According to claim 1,
    상기 약제학적으로 허용되는 첨가제가 계면활성제인 조성물. Of an additive to the pharmaceutical acceptable surface active agent composition.
  5. 제 4 항에 있어서, 5. The method of claim 4,
    상기 계면활성제가 식물성 오일과 에틸렌 글리콜의 반응 생성물, 폴리옥시에틸렌-소르비탄-지방산 에스테르, 폴리옥시에틸렌 지방산 에스테르, 폴리옥시에틸렌-폴리옥시프로필렌 블록 공중합체, 소듐 디옥틸설포숙시네이트, 소듐 라우릴 설페이트, 인지질, 프로필렌 글리콜 모노-지방산 에스테르, 프로필렌 글리콜 디-지방산 에스테르, 천연 식물성 오일 트리글리세리드와 폴리알킬렌 폴리올의 트랜스-에스테르화 반응 산물, 모노-글리세리드, 디-글리세리드 및 소르비탄 지방산 에스테르로 이루어진 군으로부터 선택된 조성물. Wherein the surfactant is a vegetable oil and a reaction product of ethylene glycol, polyoxyethylene-sorbitan-fatty acid esters, polyoxyethylene fatty acid esters, polyoxyethylene-polyoxypropylene block copolymer, sodium dioctyl tilseol sulfosuccinates, sodium lauryl sulfate, phospholipids, propylene glycol mono- group consisting of glycerides and a sorbitan fatty acid ester-fatty acid ester, propylene glycol di-fatty acid esters, and natural vegetable oil triglycerides and poly trans alkylene polyol-esterified reaction product, mono-glycerides, di a composition selected from the.
  6. (a) 이트라코나졸과 인산을 혼화한 후 이를 100 내지 170℃가 되도록 가열하여 균질하게 용융시키고, (A) after mixing itraconazole and phosphoric acid by heating them to 100 to 170 ℃ and homogeneously melted,
    (b) 이 용융물을 냉각시키면서 약제학적 첨가제를 첨가하고, (B) while the cooling of the melt added to the pharmaceutical additives, and
    (c) 이 혼합물을 실온에서 고결시켜 고형화한 후 분쇄하는 단계를 포함하는, (C) after the solidification of the mixture to anti-bonding at room temperature, comprising the step of crushing,
    이트라코나졸의 경구투여용 조성물의 제조 방법. Method of producing a composition for oral administration of itraconazole.
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US09/411,510 US6039981A (en) 1999-06-16 1999-10-04 Antifungal oral composition containing itraconazole and process for preparing same
SI200020024A SI20677A (en) 1999-06-16 2000-06-16 Antifugal oral composition containing itraconazole and process for preparation
CNB008089485A CN1170539C (en) 1999-06-16 2000-06-16 Antifungal oral composition containing itraconazole and process for preparing same
CZ20014508A CZ292146B6 (en) 1999-06-16 2000-06-16 Antifungal oral composition containing itraconazole and process for preparing thereof
AU51144/00A AU754300B2 (en) 1999-06-16 2000-06-16 Antifungal oral composition containing itraconazole and process for preparing same
TR2001/03681T TR200103681T2 (en) 1999-06-16 2000-06-16 The destructive fungi comprising itraconazole composition and method of preparing this compound
HU0201533A HU0201533A3 (en) 1999-06-16 2000-06-16 Antifungal oral composition containing itraconazole and process for preparing
DE2000627717 DE60027717T2 (en) 1999-06-16 2000-06-16 Oral composition for treating fungal itraconazole contains and the manufacturing processes thereof
PCT/KR2000/000637 WO2000076520A1 (en) 1999-06-16 2000-06-16 Antifungal oral composition containing itraconazole and process for preparing same
ES00935726T ES2262517T3 (en) 1999-06-16 2000-06-16 antifugal oral composition containing itraconazole and process for their preparation.
AT00935726T AT324893T (en) 1999-06-16 2000-06-16 Oral composition for treating fungal itraconazole contains and the manufacturing processes thereof
YUP-886/01A RS50008B (en) 1999-06-16 2000-06-16 Antifungal oral composition containing itraconazole and process for preparing same
EP20000935726 EP1185273B1 (en) 1999-06-16 2000-06-16 Antifungal oral composition containing itraconazole and process for preparing same
JP2001502853A JP3717849B2 (en) 1999-06-16 2000-06-16 Antifungal oral pharmaceutical composition containing itraconazole and a method for producing
RU2002100645A RU2216323C2 (en) 1999-06-16 2000-06-16 Antifungal composition for oral administration comprising itraconazole and method for its preparing
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